The number of thymus-derived (T) lymphocytes capable of forming rosettes with sheep erythrocytes is decreased in patients with acute viral hepatitis B and many other diseases, whereas the number of bone marrow-derived (B) lymphocytes bearing surface immunoglobulin remains normal. This results in a third, null cell, population devoid of both surface markers. Two types of null cells are known to occur in viral hepatitis B: "extrinsic" null cells generated by a humoral Rosette Inhibitory Factor (RIF) are associated with the development of chronic aggressive hepatitis; "intrinsic" null cells generated by non-humoral mechanisms are associated with chronic persistent hepatitis. The immunobiologic functions of null cells and the immunobiologic activity of RIF are unknown and their role in the pathogenesis of viral hepatitis B is unclear. We propose to examine the surface markers and functional capabilities of both types of null cells in a prospective study of patients with viral hepatitis B and to correlate these parameters of null cell immunobiology with the clinical and histopathologic manifestation of hepatocellular injury. The clinical significance and immunological activity of RIF will be examined by studying its effects on a variety of lymphocyte functions. Current efforts to isolate and characterize RIF and the T lymphocyte sheep erythrocyte receptor will be extended to determine the specific intracellular events responsible for "extrinsic" null cell generation. This investigation of null cell immunobiology should clarify the role they play in the pathogenesis of viral hepatitis B and possibly other disease states such as autoimmunity and cancer.